Cristina Gotta

Mother to child transmission of HIV infection in the era of highly active antiretroviral therapy

BACKGROUND Very low rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) are achievable with use of highly active antiretroviral therapy (HAART). We examine risk factors for MTCT in the HAART era and describe infants who were vertically infected, despite exposure to prophylactic MTCT interventions. METHODS Of the 4525 mother-child pairs in this prospective cohort study, 1983 were enrolled during the period of January 1997 through May 2004. Factors examined included use of antiretroviral therapy during pregnancy, maternal CD4 cell count and HIV RNA level, mode of delivery, and gestational age in logistic regression analysis. RESULTS Receipt of antenatal antiretroviral therapy increased from 5% at the start of the HAART era to 92% in 2001-2003. The overall MTCT rate in this period was 2.87% (95% confidence interval [CI], 2.11%-3.81%), but it was 0.99% (95% CI, 0.32%-2.30%) during 2001-2003. In logistic regression analysis that included 885 mother-child pairs, MTCT risk was associated with high maternal viral load (adjusted odds ratio [AOR], 12.1; P=.003) and elective Caesarean section (AOR, 0.33; P=.04). Detection of maternal HIV RNA was significantly associated with antenatal use of antiretroviral therapy, CD4 cell count, and mode of delivery. Among 560 women with undetectable HIV RNA levels, elective Caesarean section was associated with a 90% reduction in MTCT risk (odds ratio, 0.10; 95% CI, 0.03-0.33), compared with vaginal delivery or emergency Caesarean section. CONCLUSIONS Our results suggest that offering an elective Caesarean section delivery to all HIV-infected women, even in areas where HAART is available, is appropriate clinical management, especially for persons with detectable viral loads. Our results also suggest that previously identified risk factors remain important.

Prospective study of mother-to-infant transmission of hepatitis C virus: a 10-year survey (1990-2000)

Background. The purpose of this study was to determine the rate of vertical transmission of hepatitis C virus (HCV). We also aimed to analyze the time of clearance of maternal antibodies in the serum of non‐infected babies.

Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiency virus

Neutrophil, lymphocyte, and T-cell subset numbers and immunoglobulin levels were evaluated at birth to age 2 years in 675 children born to mothers infected with the human immunodeficiency virus type 1 (58 infected symptom-free subjects (P-1), 203 infected subjects with symptoms (P-2), and 414 uninfected subjects). The P-2 patients had (even at birth to age 1 month) lower CD4+ lymphocyte and higher IgA and IgM values than P-1 and uninfected children had. Increased IgG values (from 1 to 6 months of age) and increased CD8+ lymphocyte numbers (at 13 to 24 months of age) were also observed. The P-1 children differed from uninfected children only at 13 to 24 months of age (decreased CD4+ and increased CD8+ lymphocytes). Progressive immunologic changes were found in P-2 patients who had severe clinical conditions and in those who died. To evaluate the predictive meaning of the immunologic changes, we selected 164 children (25 P-2, 15 P-1, and 124 uninfected children) because they had been examined sequentially from birth and they were classified as in the indeterminate state of infection (P-0) at immunologic evaluations at birth to age 1 and at 1 to 6 months of age. During the 1- to 6-month period, P-2 patients had higher immunoglobulin and lower CD4+ lymphocyte values than P-1 and uninfected children had; no difference was found between P-1 and uninfected subjects. These results indicate that in infants with perinatal human immunodeficiency virus type 1 infection, immunologic abnormalities correlate with the clinical condition and are predictive of the clinical outcome rather than the infection status.

Rapid disease progression in HIV-1 perinatally infected children born to mothers receiving zidovudine monotherapy during pregnancy The Italian Register for HIV Infection in Children*

OBJECTIVE To investigate the outcome in children perinatally infected with HIV-1 whose mothers received zidovudine (ZDV) monotherapy in pregnancy. DESIGN Observational retrospective study of a prospectively recruited cohort. SETTING Italian Register for HIV Infection in Children. PATIENTS A group of 216 children perinatally infected with HIV-1, born in 1992-1997 and derived prospectively from birth: 38 children had mothers receiving ZDV monotherapy and for 178 children the mothers received no antiretroviral treatment during pregnancy. MAIN OUTCOME MEASURES The estimated probability of developing severe disease or severe immune suppression, survival probability [95% confidence interval (CI)] within 3 years, and the hazard ratio (95% CI), adjusted for year of birth, maternal clinical condition at delivery, birthweight and treatments (Pneumocystis carinii pneumonia chemoprophylaxis and/or antiretroviral therapy before the onset of severe disease, severe immune suppression or death) were compared. RESULTS Comparison of HIV-1-infected children whose mothers were treated with ZDV with children whose mothers were not treated showed that the former group had a higher probability of developing severe disease [57.3% (95% CI 40.9-74.3) versus 37.2% (95% CI 30.0-45.4); log-rank test 7.83, P = 0.005; adjusted hazard ratio 1.8 (95% CI 1.1-3.1)] or severe immune suppression [53.9% (95% CI 36.3-73.5) versus 37.5% (95% CI 30.0-46.2); log-rank test 5.58, P = 0.018; adjusted hazard ratio 2.4, (95% CI: 1.3-4.3)] and a lower survival [72.2% (95% CI 50.4-85.7) versus 81.0% (95% CI 73.7-86.5); log-rank test 4.23, P = 0.039; adjusted hazard ratio of death 1.9 (95% CI 1.1-3.6)]. CONCLUSIONS This epidemiological observation could stimulate virologic studies to elucidate whether this rapid progression depends on in utero infection or transmission of resistant virus. Findings may suggest a need to hasten HIV-1 diagnosis in infants of ZDV-treated mothers and undertake an aggressive antiretroviral therapy in those found to be infected.

Low incidence of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus

In children born to immunocompetent women, congenital toxoplasmosis almost always results from primary infection during pregnancy. However, reactivation of latent toxoplasmosis during pregnancy could occur in HIV-infected pregnant women, particularly in those who are severely immunocompromised, and result in maternal-fetal transmission of the parasite. This mode of infection has been described in case reports but the risk of transmission is unknown. Findings on toxoplasmosis are presented from the European Collaborative Study, a prospective study of children born to women known to be HIV-infected at the time of delivery. In 1058 children followed for a mean duration of 35 months, only one child developed clinical toxoplasmosis. This child was HIV-infected, severely immunocompromised, and acquired toxoplasmosis postnatally. Congenital infection was excluded serologically in a subgroup of 167 children, of whom an estimated 71 had been at risk of infection. These clinical and serological findings indicate a low general risk of maternal-fetal transmission of Toxoplasma infection in HIV-infected women. It is not possible to draw conclusions about the risk of transmission for severely immunocompromised HIV-infected women because most women in the study were asymptomatic.

Age related standards for total lymphocyte, CD4+ and CD8+ T cell counts in children born in Europe

Objective: Currently used reference values for immunologic markers in children are largely derived from cross-sectional data from historic, small sample size studies in predominantly white children. There is a lack of reliable age-related standards for immunologic markers, such as CD4+ cell counts, in particular in black children whose values according to recent reports may differ from those in white children. Standards are essential for diagnosing and monitoring childhood diseases such as pediatric human immunodeficiency virus (HIV) infection. Design: Prospective cohort study with data on 1781 uninfected children born to HIV-infected mothers in the European Collaborative Study. Methods: Age-related standards (centiles) for immunologic markers (CD4+ and CD8+ cell counts and total lymphocyte counts) up to 5 years in black and up to 10 years in white children were constructed using Generalized Additive Models for Location, Scale and Shape method, which allows for variability and skewness of the data. The optimal model was chosen according to the Akaike Information Criterion. Results: Patterns and values of total lymphocyte, CD4+ and CD8+ cell counts varied with age, especially in the first 3 years of life, but less so thereafter. Values of all 3 immunologic markers were substantially and significantly lower in black than in white children of the same age. Conclusions: We present age-related standards separately for black and white children to aid clinicians in the monitoring of childhood diseases. These standards may also contribute to the decision on an accurate cutoff for CD4+ cell counts for initiating treatment of HIV-infected children.

Use of raltegravir in a late presenter HIV-1 woman in advanced gestational age: case report and literature review.

Abstract Vertical transmission of human immunodeficiency virus (HIV) represents an important worldwide health problem and rapid decline in viral load is essential for HIV pregnant women to prevent mother to child transmission. Specific issues such as late presentation of pregnant HIV-infected women remain a clinical challenge. We present a case of an HIV-infected woman who presented to our hospital at 35 weeks of pregnancy, who was successfully treated with raltegravir-based first-line combined antiretroviral regimen. Even though there is limited information about safety and tolerability of the use of raltegravir in pregnancy, in our case this drug resulted in a rapid decline in HIV-RNA viral load, without side effects. The aim of the present study and literature review was to demonstrate that raltegravir can be a good treatment choice for very late presenting pregnant women.

Italian consensus statement on paediatric HIV infection

The objective of this document is to identify and reinforce current recommendations concerning the management of HIV infection in infants and children in the context of good resource availability. All recommendations were graded according to the strength and quality of the evidence and were voted on by the 57 participants attending the first Italian Consensus on Paediatric HIV, held in Siracusa in 2008. Paediatricians and HIV/AIDS care specialists were requested to agree on different statements summarizing key issues in the management of paediatric HIV. The comprehensive approach on preventing mother-to-child transmission (PMTCT) has clearly reduced the number of children acquiring the infection in Italy. Although further reduction of MTCT should be attempted, efforts to personalize intervention to specific cases are now required in order to optimise the treatment and care of HIV-infected children. The prompt initiation of treatment and careful selection of first-line regimen, taking into consideration potency and tolerance, remain central. In addition, opportunistic infection prevention, adherence to treatment, and long-term psychosocial consequences are becoming increasingly relevant in the era of effective antiretroviral combination therapies (ART). The increasing proportion of infected children achieving adulthood highlights the need for multidisciplinary strategies to facilitate transition to adult care and maintain strategies specific to perinatally acquired HIV infection.

Potential role of raltegravir-based therapy to induce rapid viral decay in highly viraemic HIV-infected neonates

We report safety and tolerability of raltegravir (RAL) as a forth HIV agent in two highly viraemic newborns. Raltegravir (6 mg/kg) was given orally twice daily. The other antiretrovirals were assumed according to standard dose for newborns. The first baby was born at week 36. An antiretroviral therapy consisting of zidovudine, lamivudine, and lopinavir/ritonavir was started 96 hour after delivery. Raltegravir was added at hour 120, being plasma HIV-1 RNA above 10×106 copies/ml. HIV RNA declined to 5·000 copies/ml at day 30. The second baby was born at week 40. He was started on zidovudine, lamivudine, and nevirapine at day 0, while RAL was added at day 3. Plasma HIV-1 RNA declined from 6·6×106 at birth to 52 copies/ml at day 28. RAL tolerability was good in both patients, one with gamma-glutamyltransferase increase, which normalized after RAL discontinuation. Raltegravir-based four drug regimen may be effective and well tolerated in highly viraemic HIV neonates up to 4 weeks.

Pregnancy and neonatal outcomes among a cohort of HIV-infected women in a large Italian teaching hospital: a 30-year retrospective study

The primary study objective was to investigate three decades from 1985 to 2014 of changes in pregnancies among HIV-infected women. The secondary objective was to assess risk factors associated with preterm delivery and severe small-for-gestational-age (SGA) infants in HIV-infected women. A retrospective review of deliveries among pregnant HIV-infected women at the University of Genoa and IRCCS San Martino-IST in Genoa between 1985 and 2014 was performed. Univariate and multivariable analyses were used to study the variables associated with neonatal outcomes. Overall, 262 deliveries were included in the study. An increase in median age (26 years in 1985-1994 vs. 34 years in 2005-2014), in the proportion of foreigners (none in 1985-1994 vs. 27/70 (38·6%) in 2005-2014), and a decrease in intravenous drug use (75·2% (91/121) in 1985-1994 vs. 12·9% (9/70) in 2005-2014) among pregnant HIV-infected women was observed. Progressively, HIV infections were diagnosed sooner (prior to pregnancy in 80% (56/70) of women in the last decade). An increase in combined antiretroviral therapy (cART) prescription during pregnancy (50% (27/54) in 1995-2004 vs. 92·2% (59/64) in 2005-2014) and in HIV-RNA <50 copies/ml at delivery (19·2% (5/26) in 1995-2004 vs. 82·3% (53/64) in 2005-2014) was observed. The rate of elective caesarean section from 1985 to 1994 was 9·1%, which increased to 92·3% from 2004 to 2015. Twelve (10·1%) mother-to-child transmissions (MTCT) occurred in the first decade, and six (8·3%) cases occurred in the second decade, the last of which was in 2000. Preterm delivery (<37 weeks gestation) was 5% (6/121) from 1985 to 1994 and increased to 17·1% (12/70) from 2005 to 2014. In univariate and multivariable logistic regression analyses, advancing maternal age and previous pregnancies were associated with preterm delivery (odds ratio (OR) 2·7; 95% confidence intervals (CI) 1-7·8 and OR 2·6; 95% CI 1·1-6·7, respectively). In the logistic regression analysis, use of heroin or methadone was found to be the only risk factor for severe SGA (OR 3·1; 95% CI 1·4-6·8). In conclusion, significant changes in demographic, clinical and therapeutic characteristics of HIV-infected pregnant women have occurred over the last 30 years. Since 2000, MTCT has decreased to zero. An increased risk of preterm delivery was found to be associated with advancing maternal age and previous pregnancies but not with cART. The use of heroin or methadone has been confirmed as a risk factor associated with severe SGA.